At least 25% of Americans over the age of 65 have type 2 diabetes (T2D), which, in addition to its well- recognized complications, is accompanied by a high fracture risk, particularly in elderly patients. Importantly, these fractures are associated with worse outcomes than fractures in the general population. Standard explanations, namely low bone mass and high bone turnover, do not explain how T2D adversely impacts the aging skeleton. Rather, low bone turnover, specifically reduced formation of new bone, likely predisposes to a high fracture risk. This is compounded by altered material properties of bone that together diminish bone strength and increase its propensity to fracture. Both etiologies ? reduced bone formation and altered bone material properties ? are increasingly thought to arise from the accumulation of advanced glycation endproducts (AGEs). Hence, preventing the accumulation of AGEs in bone tissue in T2D patients is a potential therapeutic strategy with likely effects in reversing bone fragility in T2D. One novel intervention is pyridoxamine, a metabolite of vitamin B6 pyridoxal phosphate. Preclinical data show that pyridoxamine has specific molecular features which provide a unique multi-pronged effect to inhibit glycation reactions and the formation of AGEs. Pyridoxamine is also a potent inhibitor of AGE accumulation and improves bone material properties in diabetic animals. Notably, while it also reduces AGEs in patients with T2D with nephropathy, there are no clinical data on possible skeletal benefits in T2D. The objective of this application is to determine whether, in a short intervention study, pyridoxamine reverses bone fragility in patients with T2D, and to use this pilot data set as a foundation for larger and longer fracture studies. Our preliminary data show strong correlations between AGE accumulation and both bone formation and bone material properties. Namely, we have shown that skin autofluorescence (SAF), a marker for tissue AGE accumulation, correlates strongly with decreased bone formation. Likewise, using a novel impact microindentation device that provides an in vivo index of cortical bone material properties, namely bone material strength index (BMSi), we show that older T2D women have increased AGE accumulation and decreased BMSi. Furthermore, T2D women with the lowest pyridoxamine stores had the highest SAFs and lowest bone formation and BMSi. Together, these data underscore our central hypothesis: that pyridoxamine treatment in older T2D patients will increase bone formation and bone material strength by inhibiting AGE accumulation. If it is confirmed that pyridoxine does improve bone formation and/or bone material properties, this data set will form the framework for large scale testing to advance the development of pyridoxamine as a therapeutic agent that should reduce fractures in aging T2D patients. In this way, this project could have a positive impact on the large and ever growing population of elderly type 2 diabetic patients.